chr2-224471097-T-C

Variant names:

• chr2-224471097-T-C
• rs17479770
• NM_003590.5:c.*3148A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003590.5(CUL3):​c.*3148A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 221,000 control chromosomes in the GnomAD database, including 8,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5403 hom., cov: 33)
  • Exomes 𝑓: 0.30 (3257 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.491
• Publications: 12 publications found

Genes affected

CUL3 (HGNC:2553): (cullin 3) This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

CUL3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without autism or seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism type 2E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000274629 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 2-224471097-T-C is Benign according to our data. Variant chr2-224471097-T-C is described in ClinVar as Benign. ClinVar VariationId is 334582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003590.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	NM_003590.5	MANE Select	c.*3148A>G		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3148A>G		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3148A>G		3_prime_UTR	Exon 15 of 15	NP_001244126.1	Q13618-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	ENST00000264414.9	TSL:1 MANE Select	c.*3148A>G		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3148A>G		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-2884T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37644 AN: 151964 Hom.: 5403 Cov.: 33

Gnomad AFR AF: 0.0916

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.302 AC: 20785 AN: 68918 Hom.: 3257 Cov.: 0 AF XY: 0.301 AC XY: 9580 AN XY: 31782

African (AFR) AF: 0.0933 AC: 308 AN: 3302

American (AMR) AF: 0.315 AC: 656 AN: 2082

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1443 AN: 4368

East Asian (EAS) AF: 0.355 AC: 3489 AN: 9830

South Asian (SAS) AF: 0.202 AC: 117 AN: 580

European-Finnish (FIN) AF: 0.180 AC: 9 AN: 50

Middle Eastern (MID) AF: 0.344 AC: 148 AN: 430

European-Non Finnish (NFE) AF: 0.305 AC: 12954 AN: 42464

Other (OTH) AF: 0.286 AC: 1661 AN: 5812

GnomAD4 genome AF: 0.248 AC: 37645 AN: 152082 Hom.: 5403 Cov.: 33 AF XY: 0.249 AC XY: 18500 AN XY: 74326

African (AFR) AF: 0.0915 AC: 3799 AN: 41538

American (AMR) AF: 0.318 AC: 4854 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3464

East Asian (EAS) AF: 0.380 AC: 1971 AN: 5182

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4818

European-Finnish (FIN) AF: 0.280 AC: 2960 AN: 10556

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20868 AN: 67940

Other (OTH) AF: 0.258 AC: 544 AN: 2112

Alfa AF: 0.296 Hom.: 2875

Bravo AF: 0.245

Asia WGS AF: 0.292 AC: 1017 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not provided (1)
-	-	1	Pseudohypoaldosteronism type 2E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.1
DANN	Benign	0.82
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17479770; hg19: chr2-225335814;